When an organ in organisms is damaged, for example, by blood flow disorder, ischemia reperfusion injury, hypertension, hyperglycemia, hyperlipemia, pharmaceutical agent or viral infection, there works an organism defense mechanism by, for example, T lymphocytes, macrophages, NK cells, fibroblasts, B lymphocytes and antibodies, complements, etc. Particularly, T cells and macrophages have an important participation in the said organism defense mechanism.
Damaged organ tissues show any of the responses of necrosis, natural death or self-regeneration depending upon the degree of the damage. At that time, chemokines, cytokines, etc. are expressed from the said tissues to promote self-proliferation and regeneration and, at the same time, organism defense mechanism of the host is activated as well. It has been presumed that the outcome whether the damaged tissues result in necrosis or natural death by way of atrophy and fibrosis or they result in regeneration of tissues is the result of the interaction of both.
For example, there are several reports for the studies that, in the damaged renal tissue lesions, the damaged renal tissue cells express tissue-specific chemokine, cytokine or adhesion factor depending upon the damaged area, etc. whereby the response is exhibited.
Wada, et al. reported that, in human crescentic glomerulonephritis, MIP-1α of chemokine is expressed in glomerular cellular crescents in an acute stage while, in interstitial tissues of the cases of fibrous crescents in a chronic stage, MCP-1 is expressed (Wada T., Furuichi K., Segawa-Takeda C., Shimizu M., Sakai N., Takeda S. I., Takasawa K., Kida H., Kobayashi K. I., Mukaida N., Ohmoto Y., Matsushima K., Yokoyama H.: MIP-1α and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int., 56: 995-1003, 1999.
Matsuda, et al. reported that, in model rats suffering from crescentic glomerulonephritis, P-secretin and L-secretin are expressed in a discriminated manner in glomerular endothelial cells and in interstitial tissues from urinary tubule, respectively (Michihiro Matsuda, Kenichi Shikata, Daisuke Ogawa, Shinichi Okada, Yasushi Shikata, Atsushi Wada. and Hiroshi Makino: Mechanism of Induction of Infiltration of Leucocytes to Renal Tissues by Secretin, Nippon Jinzo Gakkaishi, 42: 213, 2000).
Tesch, et al. reported that, when nephrotoxic serum nephritis model was prepared in MCP-1 knockout mice and expression of MCP-1 was checked, the expression of MCP-1 in the damaged site of urinary tubule was weak as compared with a wild type while the expression of MCP-1 in the glomerular lesion had no difference from the wild type. They also reported that, in the knockout mice where expression of MCP-1 was weak, infiltration of macrophage decreased whereby MCP-1 showed the result that it participated in migration of macrophage while, in terms of degree of proteinuria in an acute stage, there is no difference between both and there was no relation between tissue damage and macrophage infiltration in an acute stage (Tesch G. H., Schwarting A., Kinoshita K., Rolins B. J., Kelly V. R.: Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephritic serum nephritis, J. Clin. Invest. 1999, 103: 73-80.).
Not only in kidney but also in exocrine gland and islet of Langerhans of pancreas, there is noted a difference in chemokine-productive response concerning the lesion after the organ tissue damage corresponding to the damaged tissue.
Cameron, et al. reported that, in the mice where nonobese type I diabetes was spontaneously occurred, promotion of the expression of MIP-1α and lowering of the expression of MCP-1 were noted among chemokines in islets of Langerhans and that there was a correlation between damage of islets of Langerhans and onset of diabetes (Cameron M. J., Arreaza G. A., Grattan M., Meagher C., Sharif S., Burdick M. D., Strieter R. M., Cook D. N., Delovitch T. L.: Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes, J. Immunol., 2000, 165: 1102-10).
In the meanwhile, Andoh, et al. investigated the expression of chemokines in pancreatitis tissues of human acute pancreatitis cases. They reported that, in acute pancreatitis, expression of MIP-1α was not noted but expression of MCP-1, IL-8 and RANTES was noted in exocrine, acinar and ductal interstitial pancreas tissues (Andoh A., Takaya H., Saotome T., Shimada M., Hata K., Araki Y., Nakamura F., Shintani Y., Fujiyama Y., Bamba T.: Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts, Gastroenterology, 2000, 119: 211-9).
As mentioned above, it was suggested in human clinical studies and experimental study models using animals that, in progressive lesion noted after the organic damage, effector macrophage participated therein corresponding to the damaged tissues.
Up to now, therapy of steroids, etc. has been carried out for progressive lesion after organic damage. However, since steroidal preparations non-selectively suppress the macrophage, they also suppress the response of even the macrophage participating in the reaction for tissue regeneration at the same time whereby organism defensive mechanism including the regeneration is lessened. In addition, new tissue damage is induced resulting in lesion and, as a result, there is a problem that effector macrophage mediated by the expression of chemokines and cytokines is actively induced whereby the inherent lesion is further worsened. As such, the conventional therapy of steroids has no selectivity in the action, and administration of high dose is necessary for the therapy of the lesion whereby the side effect is remarkable. In addition, there is a difficulty that a continuous therapy by steroids for a long period is accompanied by a severe side effect.
On the other hand, like the progressive lesion noted after the above-mentioned organic damage, organism defense mechanism by T cells, macrophages, etc. participates in rejection in the transplantation of organ, skin or the like. Until now, there have been known many compounds having an immunosuppressive action and, for example, compounds represented by the formula (8) (in which R1 is an optionally substituted phenyl group; R2 is an optionally esterified carboxyl group; and X is oxygen atom or optionally oxidized sulfur atom) have been known to be useful as a γ-lactone immunosuppressant (Japanese Patent Laid-Open No. 04/338,331). However, it is to be still improved so as to show a selective action to target organs or tissues or so as to show stronger immunosuppressive action.